肝脏中Zα-抗胰蛋白酶聚合的结构基础。
The structural basis for Z α-antitrypsin polymerization in the liver.
作者信息
Faull Sarah V, Elliston Emma L K, Gooptu Bibek, Jagger Alistair M, Aldobiyan Ibrahim, Redzej Adam, Badaoui Magd, Heyer-Chauhan Nina, Rashid S Tamir, Reynolds Gary M, Adams David H, Miranda Elena, Orlova Elena V, Irving James A, Lomas David A
机构信息
UCL Respiratory, University College London, 5 University Street, London WC1E 6JF, UK.
Institute of Structural and Molecular Biology, University College London, Gower Street, London WC1E 6BN, UK.
出版信息
Sci Adv. 2020 Oct 21;6(43). doi: 10.1126/sciadv.abc1370. Print 2020 Oct.
The serpinopathies are among a diverse set of conformational diseases that involve the aberrant self-association of proteins into ordered aggregates. α-Antitrypsin deficiency is the archetypal serpinopathy and results from the formation and deposition of mutant forms of α-antitrypsin as "polymer" chains in liver tissue. No detailed structural analysis has been performed of this material. Moreover, there is little information on the relevance of well-studied artificially induced polymers to these disease-associated molecules. We have isolated polymers from the liver tissue of Z α-antitrypsin homozygotes (E342K) who have undergone transplantation, labeled them using a Fab fragment, and performed single-particle analysis of negative-stain electron micrographs. The data show structural equivalence between heat-induced and ex vivo polymers and that the intersubunit linkage is best explained by a carboxyl-terminal domain swap between molecules of α-antitrypsin.
丝氨酸蛋白酶抑制剂病属于多种构象疾病，这些疾病涉及蛋白质异常自组装成有序聚集体。α-抗胰蛋白酶缺乏症是典型的丝氨酸蛋白酶抑制剂病，是由α-抗胰蛋白酶的突变形式以“聚合物”链的形式在肝组织中形成和沉积所致。尚未对这种物质进行详细的结构分析。此外，关于经过充分研究的人工诱导聚合物与这些疾病相关分子的相关性的信息很少。我们从接受过移植的Zα-抗胰蛋白酶纯合子（E342K）的肝组织中分离出聚合物，用Fab片段对其进行标记，并对负染电子显微镜照片进行单颗粒分析。数据显示热诱导聚合物和体内聚合物在结构上具有等效性，并且亚基间的连接最好用α-抗胰蛋白酶分子之间的羧基末端结构域交换来解释。
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